Post-traumatic stress disorder (PTSD) is a maladaptive and debilitating psychiatric disorder characterized by an extreme sense of fear at the time of trauma occurrence, with characteristic re-experiencing, avoidance, and hyperarousal symptoms in the months and years following the trauma. PTSD has a prevalence of approximately 6%, but can occur in up to 25% of subjects who have experienced severe psychological trauma, such as combat veterans, refugees, and assault victims. The differential risk determining those who do vs. those who do not develop PTSD is multi-determined: 1) it is in part genetic, with approximately a 30-40% risk heritability for PTSD following trauma; 2) it in par depends on sex, with women having approximately twice the risk as men to develop PTSD following trauma; and 3) it in part depends on past personal history, including adult and childhood trauma and psychological factors which may differentially mediate fear and emotion regulation. We have recently utilized convergent genetic approaches to identify the PACAP/PAC1R receptor pathway as being associated with PTSD and with dysregulation of conditioned fear in humans1. Further, we found that this association was only found in females, and that the primary polymorphism lay within an Estrogen Response Element. Additionally, we found that PAC1R and PACAP mRNA are induced with fear conditioning or estrogen replacement in rodent models. Together, these data strongly suggest that perturbations in the PACAP/PAC1R pathway are involved in abnormal fear responses underlying PTSD, particularly in females. We now wish to extend these data by examining the mechanisms by which estrogen and genetic polymorphisms differentially modulate fear extinction in women. This work will further our understanding of how sex-dependent processes may specifically lead to differential risk for stress-related biological responses.